One- or Two-Step Synthesis of C-8 and N-9 Substituted Purines

Article abstract of DOI:10.1021/acs.joc.7b02269

A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and hydrazine, respectively.

Full text of DOI:10.1021/acs.joc.7b02269

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One or two steps synthesis of C-8 and N-9 substituted purines.
Melanie BOLLIER, Frederique Klupsch, Perrine SIX, Laurent Dubuquoy,
Nathalie AZAROUAL, Regis Millet, and Natascha Leleu-Chavain
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02269 • Publication Date (Web): 01 Dec 2017
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One or two steps synthesis of C-8 and N-9 substituted
purines.
Mélanie Bollier,† Frédérique Klupsch,† Perrine Six,† Laurent Dubuquoy,‡ Nathalie Azaroual,§
Régis Millet,† and Natascha Leleu-Chavain*,†
†
‡
§
Univ. Lille, Inserm, ICPAL, U995 – LIRIC – Lille Inflammation Research International Center, 3 rue du Pr Laguesse BP8, F-59006 Lille,
France
Univ. Lille, Inserm, CHU Lille, U995 – LIRIC – Lille Inflammation Research International Center, faculté de médecine, Place de Verdun, F-
59045, Lille Cedex, France
Univ. Lille, CHU Lille, EA 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, 3 rue du Pr
Laguesse BP8, F-59006 Lille, France
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ABSTRACT
A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted
purines was developed. The present procedure describes annulation reactions in one or two
steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-
disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-
purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-
1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one
step using formic acid, urea, guanidine carbonate and phenylisocyanate, respectively.
Whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-
dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and
hydrazine, respectively.
Imidazo[4,5-d]pyrimidines better known as purines, are the most ubiquitous nitrogen
containing heterocycles in nature. Among the greatest prominent examples are adenine and
guanine in nucleic acids, uric acid or caffeine. Due to their implication in many biochemical
pathways, purines fascinate pharmacochemists because of their great potential as biological
tool and therapeutic agent. Purine-based compounds are currently used in the treatment of a
wide range of diseases such as cancers (6-mercaptopurine, thioguanine), viral diseases
(acyclovir, abacavir), neuropsychiatric disorders, neurodegenerative diseases, inflammatory
diseases (theophylline, azathioprine, 6-mercaptopurine), tuberculosis or impotence.1
Hermann Emil Fischer achieved the first synthesis of imidazo[4,5-d]pyrimidine in 1898.2
Since then, several synthetic routes to purine derivatives have been reported in literature.3–7
For instance, 1,3,8-trisubstituted xanthines and 2,8-disubstituted adenines are obtained
through cyclization of pyrimidine derivatives.1 Another illustration are reactions like SNAr-type
substitutions8 or coupling reactions9,10 on appropriately activated purines providing access to
polyfunctionalized purines at positions 2, 6, 8 or 9. However, there have been very few
publications describing 8,9-disubstituted purines to date. The few synthesis pathways that
have been reported are generally limited by structural restrictions. Currently, three main
approaches have been described (Scheme 1).
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Scheme 1. Synthetic routes to obtain 8,9-disubsituted purines: comparison of the
described method to the reported methods
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The first one starts directly from purine structures (pathway 1).9,11–14 Despite the good yields
for the two steps, the first pathway cannot really be considered as a purine synthesis, strictly
speaking, because no purine scaffold is build. This synthesis route uses either cross-
coupling reactions (palladium,11,12,14 iron,9 metal-free using tBuOOtBu),15 or lithiation
reactions followed by an halogen trapping.13 These strategies have the disadvantage to use
harsh reaction conditions, to be toxic, expensive, not environmentally friendly, to generate
regioselectivity problems, and thereby to be unsuitable for the development of
pharmaceutical compounds.16
The second way starts from pyrimidines (pathway 2).17–20 This well-established strategy
provides 8,9-disubstituted purines either by the reaction of pyrimidine-4,5-diamines with
orthoesters19,20 or acyl chlorides,17 or by refluxing 5-nitropyrimidin-4-amines in phenyl ether.18
However, the structure of the synthesized purine (R’ and R’’) is limited to the nature of the
starting pyrimidine.
Thus, the major drawback of the first two pathways is the restriction in the structure diversity
of the resulting purines. To overcome this structural limitation and the problems encountered
with pathways 1 and 2, construction of the six-membered ring can be achieved from
imidazole derivatives (pathway 3).21–23 Using this approach, various bicycles can be
synthesized (e.g. 8,9-dimethyl-2-substituted-9H-purine-6-carboxamide, 8,9-dimethyl-2-
substituted-9H-purine-6-carbonitrile, 2,6,9-trisubstituted-8-(substitutedthio)-9H-purine, 8,9-
dimethyl-2-(trifluoromethyl)-5H-purin-6(9H)-one, 8,9-dimethyl-6,6-disubstituted-6,9-dihydro-
1H-purin-2(3H)-one, 1H-purine-2,6(3H,7H)-dione, 1H-purin-6(9H)-one). Nevertheless, to the
best of our knowledge, R1 and R2 are mostly limited to methyl groups.21,23 Miscellaneous
substituents can be introduced but it requires the previous synthesis of the starting imidazole
in 6 steps (Scheme 1).22 Therefore, the search for new rapid routes to 8,9-disubstituted
purines remains a synthetic challenge.
Herein, we report a novel and efficient strategy to obtain a large diversity of C-8 and N-9
substituted purines in one or two steps from 5-amino-imidazole-4-carbonitriles. Because 5-
amino-imidazole-4-carbonitriles contain a highly reactive β-enaminonitrile system, they can
rapidly yield to new heterocycles.
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β-Enaminonitriles have been demonstrated as an important and versatile system to yield
heterocycles rapidly. Thereby, association of an enaminonitrile system with an imidazole ring
was applied to provide purines in few steps. Preliminary work was to synthesize N-1 and C-2
substituted 5-aminoimidazole-4-carbonitriles 1-8 as enaminonitrile system, through the
multicomponent condensation reaction of aminomalononitrile, trimethylorthoester and
primary amine in two steps (Scheme 2, 42-78%).24 First, aminomalononitrile reacts with
trimethylorthoester in THF at reflux for 3 h in the presence of triethylamine. Then, the
reaction between the formed intermediate and a primary amine at 20 °C for 15 h affords the
desired 5-aminoimidazole-4-carbonitriles 1-8 in good yields (42-78%).
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Scheme 2. Synthesis of 5-amino-imidazole-4-carbonitriles 1-8
Scheme 3. Synthesis of C-8 and N-9 substituted purines in one or two steps from 5-
amino-imidazole-4-carbonitriles
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Starting from intermediates 1 to 8, annulation of imidazoles to various purines was
investigated. Three procedures were used including cyclisation with boiling formic acid,25 or
solvent-free cyclisation with urea25,26 and guanidine carbonate25 to provide 8,9-disubstituted-
6,9-dihydro-1H-purin-6-ones (9-14, 37-78%), 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-
2-ones (15-20, 21-47%), and 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines (21-24, 23-
62%), respectively (Scheme 3). To improve the reaction yields for compounds 15-20, we
investigated the use of solvent and base.27 Imidazole and urea were refluxed in ethanol with
sodium ethanolate or in NMP for 4-6 h without success. Thus, we decided to boost the
reaction using microwaves irradiation. The use of microwave energy is well known to afford
better reaction yields and shorter reaction times than conventional heating.28 Different
irradiation conditions have been explored (temperature varying from 120 to 200 °C, power
level from 140 to 300 W, open or closed vessel) without improving reaction yields.
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Figure 1. Chemical structure of unexpected products 41-45
Imidazole annulation provided also the synthesis of 6-imino-1-phenyl-8,9-disubstituted-6,9-
dihydro-1H-purin-2-(3H)-ones (25-26) starting from 5-aminoimidazole-4-carbonitriles (1-2).
To synthesize products 25-26, imidazole 1 or 2 and phenylisocyanate (1 equiv.) were
refluxed in pyridine for 24 h. Unfortunately, desired compounds 25-26 were not obtained.29
Four products were detected on the LC-MS spectrum at m/z 212.1, 313.1, 450.2 and 543.3
(starting from compound 1) and at m/z 212.1, 313.1, 534.3 and 627.3 (starting from
compound 2). We suggest that these 4 products correspond to 1,3-diphenylurea 41, 1,3-
diphenyl-1-(phenylcarbamoyl)urea 42, product 43 and product 44, respectively (Figure 1).
Indeed, we assume that cyclization does not occurred and the open form 1-(4-cyano-1,2-
disubstituted-3H-imidazol-5-yl)-3-phenylurea 45 of the desired product is formed instead.
This open form may react with the starting imidazole left to give compound 43 and aniline.
We assume that the released aniline react either with 43 to form 44, or with 2 molecules of
phenylisocyanate to give 1,3-diphenylurea 41 and 1,3-diphenyl-1-(phenylcarbamoyl)urea 42,
successively.
Table 1. Effect of solvent, base and quantity of phenylisocyanate on the synthesis of
6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26
Compound
25 or 26
25
Starting material
Phenylisocyanate
1 equiv
Solvent and base
Pyridine
Time
24 h
5 d
T °C
reflux
reflux
rt
Yield %
-
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0
0
1 equiv
Pyridine (volume x 6)
DCM + TEA
25 or 26
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1 equiv
5 d
6-7
slowly added during
12 h at -50 °C
25
10 equiv
THF + TEA
5 d
rt
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The formation of unexpected products prompted us to promote the intramolecular cyclisation
over the intermolecular reaction by diluting 6 times the reaction medium without success
(Table 1). Another procedure using dichloromethane with a few drops of triethylamine at
room temperature for 5 days afforded the desired cyclized form with 6-7% yield (Scheme
3).30 Encouraged by this promising result, 10 equivalents of phenylisocyanate were used and
the starting imidazole was slowly added during 12 h at -50 °C. Furthermore, DCM was
replaced by THF to circumvent the problem of starting material solubility in DCM at -50 °C.
Under these conditions, reaction yield for 9-benzyl-6-imino-8-methyl-1-phenyl-6,9-dihydro-
1H-purin-2-(3H)-one 25 was improved to 13% (Table 1).
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In our attempts to form substituted purines, two additional procedures using the
enaminonitrile cyclization strategy were carried out. 8,9-disubstituted-9H-purin-6-amines 27-
31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two
steps.31 For compounds 27-31, N,N-dimethylmethanimidamide intermediates 34-38 were first
synthesized by the reaction of starting imidazoles 1-3, 5-6 with N,N-dimethylformamide
dimethyl acetal (DMF-DMA) at 70 °C under microwave irradiation (200 W) during 15 min in a
sealed vessel (83-97%). Ammonia is generated in situ by microwave-assisted degradation of
formamide and can thus perform a nucleophilic attack on intermediates 34-38 followed by
intramolecular cyclization and tautomerization to lead to 9H-purin-6-amines 27-31 (68-74%,
Scheme 3).
Scheme 4. Synthesis of 6-imino-6,9-dihydro-1H-purin-1-amines 32-33
The compounds 32-33 were synthesized from ethyl-N-(4-cyano-1H-imidazol-5-yl)formimidate
intermediates 46-47, previously obtained by reaction of starting imidazole (1 or 2) and an
excess of triethylorthoformate.32 Because these formimidate derivatives are easily
hydrolyzable by water to the corresponding N-(4-cyano-1H-imidazol-5-yl)formimidic acids,
they were involved in the next step without further purification. One equivalent of 99%
hydrazine monohydrate was stirred with intermediates 46-47 for 3 h at 0-5 °C to give
compounds 32-33 in moderate yields (25-26%). When an excess of 99% hydrazine
monohydrate is used, iminoesters were reduced to starting imidazoles 1-2 by the preferential
elimination of ethylformate hydrazone instead of the cyclization into 6-imino-8,9-
disubstituted-6,9-dihydro-1H-purin-1-amines 32-33. Despite the use of one equivalent of 99%
hydrazine monohydrate, the formation of a side product was also observed. Indeed, residual
triethylorthoformate from the first step reacts with the 6-imino-purin-1-amines 32-33 to give
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2,3-disubstituted-3H-[1,2,4]triazolo[5,1-i]purines 48-49 (Scheme 4).33 To prevent the
formation of these tricyclic by-products, we decided to first synthesize Boc-protected
compounds 39-40 (60-64%), whose N-protecting group was next cleaved with TFA (68-86%)
to give 6-imino-1H-purin-1-amines 32-33 (Scheme 4). As compared with the first synthesis
route, this N-protection based strategy led to a yield increase from 25-26% to 41-55%.
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In conclusion, we described a new convenient and efficient strategy to synthesized 8,9-
disubstituted purines. The advantage of our approach is to offer a large diversity of bicycles
obtained in one or two steps from the common 5-aminoimidazole-4-carbonitrile such as
hypoxanthine, isoguanine, adenine and 2-aminoadenine.
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EXPERIMENTAL SECTION
General Information. All commercial reagents and solvents were used without further
purification. Analytical thin-layer chromatography was performed on pre-coated Polygram Sil
G/UV254 plates (Macherey-Nagel®); the spots were located by UV (254 and 366 nm). Silica
gel 60 230–400 mesh purchased from Merck® was used for column chromatography.
Preparative HPLC were performed using an OmniSpher C18 column 10 µm particle size,
dimensions 41 mm x 250 mm, on a Varian SD-1 prepstar equipped with a UV detector set at
254 nm. The following solvent system was used: eluent (A): 0.1% formic acid in H2O, eluent
(B) 100% CH3CN ; 10% eluent B for 5 min, then a gradient run to 70% eluent B over the next
20 min. The microwave reactions were performed using a CEM DiscoverSP, in sealed
reaction vials, and the temperature was monitored using IR temperature sensor. All melting
1
points were determined with a Büchi 535® capillary apparatus and remain uncorrected. H-
and 13C-NMR spectra were obtained using a Bruker® 300 MHz or 500 MHz spectrometer,
chemical shifts (δ) are expressed in ppm relative to tetramethylsilane used as an internal
standard, J values are in hertz, and the splitting patterns are designated as follows: s, singlet;
d, doublet; t, triplet; q, quadruplet; quint, quintet; sex, sextuplet; m, multiplet. All compounds
were analyzed by HPLC-MS on a HPLC combined with a Surveyor MSQ (Thermo Electron®)
equipped with an electrospray ionisation (ESI) or atmospheric pressure chemical ionization
(APCI)-source. A Micromass (Waters, Manchester, UK) high resolution TOFMS with an ESI
source was used to detect the analytes of interest in positive mode or negative mode. The
TOF analyser was used in V mode at 9000 mass resolution. The purity of all compounds was
determined by HPLC using a Chromazing column and a WATERS 600 pump chromatograph
equipped with a WATERS 2487 dual absorption wavelength UV detector (λ = 254 nm and
366 nm). Retention time was obtained with flow rates of 1 mL/min. The acquisition time is 20
min.
General Procedure for the Synthesis of 5-amino-1,2-disubstituted-1H-imidazole-4-
carbonitriles (1-8). To a solution of aminomalononitrile p-toluenesulfonate (5.9 mmol) in
THF (30 mL) was added triethylamine (7.1 mmol). The mixture was stirred at room
temperature for 30 min. To this solution was added the corresponding trimethyl orthoester
(8.3 mmol) and the solution was refluxed for 3 h. After return to room temperature,
triethylamine (7.1 mmol) and the corresponding primary amine (7.1 mmol) were added. The
solution was stirred at room temperature for 15 h. The solvent was removed under reduced
pressure. The residue was dissolved in dichloromethane (30 mL), washed with saturated
aqueous Na2CO3 (3 x 20 mL) and saturated aqueous NaCl (20 mL). The organic layer was
dried over MgSO4 and the solvent was evaporated under reduced pressure.
5-Amino-1-benzyl-2-methyl-1H-imidazole-4-carbonitrile (1). The crude residue was
purified on silica gel chromatography eluting with 20% cyclohexane in ethyl acetate.
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Compound 1 (0.92 g, Y = 73%) was isolated as a beige solid ; mp = 172-174 °C. H NMR
(CDCl3, 300 MHz) δ 7.39-7.32 (m, 3H), 7.07-7.04 (m, 2H), 4.99 (s, 2H), 4.12 (s, 2H), 2.27 (s,
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3H). 13C NMR (CDCl3, 75 MHz) δ 145.5 (C), 141.1 (C), 134.2 (C), 129.5 (2CH), 128.6 (CH),
126.0 (2CH), 115.9 (C), 94.3 (C), 46.6 (CH2), 13.57 (CH3). LC-MS (APCI+) m/z 213.1 [M+H]+.
HRMS (ESI-TOF) m/z [M+H]+ calcd for C12H11N4 213.1135 ; found 213.1137.
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5-Amino-1-benzyl-2-butyl-1H-imidazole-4-carbonitrile (2). The crude residue was purified
on silica gel chromatography eluting with 50% cyclohexane in ethyl acetate. Compound 2
(0.99 g, Y = 66%) was isolated as a beige solid ; mp = 120-122 °C. H NMR (CDCl3, 300
1
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MHz) δ 7.43-7.33 (m, 3H), 7.06-7.04 (m, 2H), 5.00 (s, 2H), 3.69 (s, 2H), 2.58 (t, 2H, J = 7.8
Hz), 1.60 (quint, 2H, J = 7.8 Hz), 1.35 (sex, 2H, J = 7.3 Hz), 0.90 (t, 3H, J = 7.3 Hz). 13C NMR
(CDCl3, 75 MHz) δ 145.3 (C), 144.8 (C), 134.4 (C), 129.5 (2CH), 128.5 (CH), 125.9 (2CH),
116.0 (C), 94.6 (C), 46.3 (CH2), 29.4 (CH2), 27.0 (CH2), 22.3 (CH2), 13.57 (CH3). LC-MS
(APCI+) m/z 255.0 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C15H19N4 255.1606 ; found
255.1604.
5-Amino-2-methyl-1-phenylethyl-1H-imidazole-4-carbonitrile (3). The crude residue was
purified on silica gel chromatography eluting with 20% cyclohexane in ethyl acetate.
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Compound 3 (1.04 g, Y = 78%) was isolated as a beige solid ; mp = 175-177 °C. H NMR
(CDCl3, 300 MHz) δ 7.33-7.31 (m, 3H), 7.04-7.01 (m, 2H), 3.97 (t, 2H, J = 6.3 Hz), 3.19 (s,
2H), 2.96 (t, 2H, J = 6.3 Hz), 2.16 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 145.2 (C), 140.9 (C),
137.0 (C), 129.3 (2CH), 128.9 (2CH), 127.6 (CH), 116.0 (C), 94.7 (C), 45.1 (CH2), 35.8
(CH2), 13.3 (CH3). LC-MS (APCI+) m/z 227.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C13H15N4 227.1291 ; found 227.1295.
5-Amino-2-butyl-1-phenylethyl-1H-imidazole-4-carbonitrile (4). The crude residue was
purified on silica gel chromatography eluting with 40% cyclohexane in ethyl acetate.
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Compound 4 (1.14 g, Y = 72%) was isolated as a beige solid ; mp = 90-92 °C. H NMR
(CDCl3, 300 MHz) δ 7.33-7.31 (m, 3H), 7.04-7.01 (m, 2H), 3.97 (t, 2H, J = 6.4 Hz), 3.15 (s,
2H), 2.96 (t, 2H, J = 6.4 Hz), 2.42 (t, 2H, J = 7.8 Hz), 1.74-1.64 (m, 2H), 1.40 (sex, 2H, J =
7.5 Hz), 0.94 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3, 75 MHz) δ 145.3 (C), 144.7 (C), 137.1 (C),
129.2 (2CH), 128.9 (2CH), 127.6 (CH), 116.1 (C), 94.5 (C), 44.8 (CH2), 36.0 (CH2), 29.2
(CH2), 26.7 (CH2), 22.4 (CH2), 13.7 (CH3). LC-MS (APCI+) m/z 269.1 [M+H]+. HRMS (ESI-
TOF) m/z [M+H]+ calcd for C16H21N4 269.1761 ; found 269.1761.
5-Amino-1-phenylethyl-2-propyl-1H-imidazole-4-carbonitrile (5). The crude residue was
purified on silica gel chromatography eluting with 50% cyclohexane in ethyl acetate.
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Compound 5 (1.04 g, Y = 69%) was isolated as a beige solid ; mp = 112-114 °C. H NMR
(CDCl3, 300 MHz) δ 7.32-7.30 (m, 3H), 7.04-7.01 (m, 2H), 3.97 (t, 2H, J = 6.4 Hz), 3.14 (s,
2H), 2.96 (t, 2H, J = 6.4 Hz), 2.40 (t, 2H, J = 6.1 Hz), 1.73 (sex, 2H, J = 7.6 Hz), 1.01 (t, 3H, J
= 7.4 Hz). 13C NMR (CDCl3, 75 MHz) δ 145.3 (C), 144.5 (C), 137.1 (C), 129.3 (2CH), 128.9
(2CH), 127.6 (CH), 116.0 (C), 94.5 (C), 44.7 (CH2), 36.0 (CH2), 28.9 (CH2), 20.5 (CH2), 13.9
(CH3). LC-MS (APCI+) m/z 255.2 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C15H19N4 255.1604 ; found 255.1607.
5-Amino-1-(adamantan-1-ylmethyl)-2-methyl-1H-imidazole-4-carbonitrile (6). The crude
residue was purified on silica gel chromatography eluting with 50% cyclohexane in ethyl
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acetate. Compound 6 (1.3 g, Y = 61%) was isolated as a beige solid ; mp = 239-241 °C. H
NMR (DMSO, 300 MHz) δ 5.93 (s, 2H), 3.50 (s, 2H), 2.15 (s, 3H), 1.92 (s, 3H), 1.65-1.51 (m,
12H). 13C NMR (DMSO, 75 MHz) δ 149.8 (C), 140.4 (C), 118.4 (C), 88.5 (C), 53.6 (CH2),
40.2 (3 CH2), 36.6 (3 CH2), 36.4 (C), 28.0 (3 CH), 14.7 (CH3). LC-MS (ESI) m/z 271.2
[M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C16H23N4 271.1917 ; found 271.1917.
5-Amino-2-butyl-1-(propyl)-1H-imidazole-4-carbonitrile (7). The crude residue was
purified on silica gel chromatography eluting with 40% ethyl acetate in cyclohexane.
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Compound 7 (510 mg, Y = 42%) was isolated as a beige solid ; mp = 102-104 °C. H NMR
(DMSO, 300 MHz) δ δ 6.03 (s, 2H), 3.67 (t, 2H, J = 7.6 Hz), 2,46 (t, 2H), 1.62-1.47 (m, 4H),
1.39-1.26 (sex, 2H, J = 7.4 Hz), 0.90-0.81 (m, 6H). 13C NMR (DMSO, 75 MHz) δ 148.4 (C),
142.8 (C), 118.5 (C), 88.6 (C), 43.5 (CH2), 29.2 (CH2), 26.2 (CH2), 22.5 (CH2), 22.2 (CH2),
14.2 (CH3), 11.2 (CH3). LC-MS (ESI) m/z 207.2 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd
for C11H19N4 207.1604 ; found 207.1614.
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5-Amino-2-methyl-1-(prop-2-yn-1-yl)-1H-imidazole-4-carbonitrile (8). The crude residue
was purified on silica gel chromatography eluting with 50% cyclohexane in ethyl acetate.
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Compound 8 (605 mg, Y = 48%) was isolated as a beige solid ; mp = 172-174 °C. H NMR
(DMSO, 300 MHz) δ 6.21 (s, 2H), 4.68 (d, 2H, J = 2.5 Hz), 3.41 (t, 1H, J = 2.5 Hz), 2.20 (s,
3H). 13C NMR (DMSO, 75 MHz) δ 148.2 (C), 139.4 (C), 118.0 (C), 88.4 (C), 78.2 (C), 75.8
(CH), 32.0 (CH2), 13.5 (CH3). LC-MS (ESI) m/z 161.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+
calcd for C8H9N4 161.0822 ; found 161.0822.
General Procedure for the Synthesis of 8,9-disubstituted-6,9-dihydro-1H-purin-6-ones
(9-14). 5-Amino-1,2-disubstituted-1H-imidazole-4-carbonitrile (1-4, 6 or 8) (3.8 mmol) was
dissolved in formic acid (3 mL) and the mixture was refluxed for 15 h. After return to room
temperature, the mixture was poured into water (30 mL). The resulting precipitate was
filtered and washed with water.
9-Benzyl-8-methyl-6,9-dihydro-1H-purin-6-one (9). The precipitate was recrystallized from
DMF/H2O (1:1). Compound 9 (Y = 78%, 710 mg from 800 mg (3.8 mmol) of 1) was isolated
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as a green solid ; mp > 250 °C. H NMR (DMSO, 300 MHz) δ 12.26 (s, 1H), 8.01 (s, 1H),
7.34-7.30 (m, 3H), 7.18-7.15 (m, 2H), 5.35 (s, 2H), 2.36 (s, 3H). 13C NMR (DMSO, 75 MHz) δ
156.7 (C), 149.8 (C), 148.4 (CH), 145.7 (C), 136.9 (C), 129.4 (2CH), 128.2 (CH), 127.4
(2CH), 123.1 (C), 45.7 (CH2), 14.1 (CH3). LC-MS (APCI+) m/z 241.1 [M+H]+. HRMS (ESI-
TOF) m/z [M+H]+ calcd for C13H13N4O 241.1084 ; found 241.1078.
9-Benzyl-8-butyl-6,9-dihydro-1H-purin-6-one (10). Compound 10 (Y = 72%, 640 mg from
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800 mg (3.1 mmol) of 2) was isolated as a beige solid ; mp = 222-224 °C. H NMR (DMSO,
300 MHz) δ 12.25 (s, 1H), 8.00 (s, 1H), 7.33-7.27 (m, 3H), 7.16-7.13 (m, 2H), 5.36 (s, 2H),
2.66 (t, 2H, J = 7.5 Hz), 1.56 (quint, 2H, J = 7.5 Hz), 1.29 (sex, 2H, J = 7.5 Hz), 0.80 (t, 3H, J
= 7.1 Hz). 13C NMR (DMSO, 75 MHz) δ 156.8 (C), 151.6 (C), 149.7 (C), 145.6 (CH), 137.1
(C), 129.2 (2CH), 128.1 (CH), 127.2 (2CH), 123.2 (C), 45.5 (CH2), 28.9 (CH2), 26.7 (CH2),
22.1 (CH2), 14.1 (CH3). LC-MS (APCI+) m/z 283.1 [M+H]+. HRMS (ESI-TOF) m/z [M+Na]+
calcd for C16H18N4ONa 305.1383 ; found 305.1376.
8-Methyl-9-phenylethyl-6,9-dihydro-1H-purin-6-one (11). Compound 11 (Y = 68%, 610 mg
from 800 mg (3.5 mmol) of 3) was isolated as a beige solid ; mp > 250 °C. 1H NMR (DMSO,
300 MHz) δ 12.18 (s, 1H), 7.97 (s, 1H), 7.28-7.18 (m, 3H), 7.08-7.04 (m, 2H), 4.29 (t, 2H, J =
7.0 Hz), 3.01 (t, 2H, J = 7.0 Hz), 2.11 (s, 3H). 13C NMR (DMSO, 75 MHz) δ 156.7 (C), 149.5
(C), 148.3 (C), 145.3 (CH), 138.3 (C), 129.3 (2CH), 128.9 (2CH), 127.1 (CH), 123.1 (C), 44.6
(CH2), 35.6 (CH2), 13.6 (CH3). LC-MS (APCI+) m/z 255.1 [M+H]+. HRMS (ESI-TOF) m/z
[M+H]+ calcd for C14H15N4O 255.1240 ; found 255.1245.
8-Butyl-9-phenylethyl-6,9-dihydro-1H-purin-6-one (12). Compound 12 (Y = 78%, 690 mg
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from 800 mg (3.0 mmol) of 4) was isolated as a beige solid ; mp = 215-217 °C. H NMR
(DMSO, 300 MHz) δ 12.18 (s, 1H), 7.98 (s, 1H), 7.25-7.20 (m, 3H), 7.06-7.03 (m, 2H), 4.29
(t, 2H, J = 7.4 Hz), 3.02 (t, 2H, J = 6.9 Hz), 2.36 (t, 2H, J = 7.6 Hz), 1.52 (quint, 2H, J = 7.3
Hz), 1.27 (sex, 2H, J = 7.6 Hz), 0.84 (t, 3H, J = 7.3 Hz). 13C NMR (DMSO, 75 MHz) δ 156.7
(C), 151.8 (C), 149.4 (C), 145.2 (CH), 138.3 (C), 129.3 (2CH), 128.9 (2CH), 127.1 (CH),
123.2 (C), 44.3 (CH2), 35.7 (CH2), 28.9 (CH2), 26.2 (CH2), 22.2 (CH2), 14.1 (CH3). LC-MS
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(APCI+) m/z 297.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C17H21N4O 297.1710 ;
found 297.1696.
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9-(Adamantan-1-ylmethyl)-8-methyl-6,9-dihydro-1H-purin-6-one (13). Compound 13 (Y =
69%, 303 mg from 400 mg (1.5 mmol) of 6) was isolated as a beige solid ; mp > 250 °C. 1H
NMR (DMSO, 300 MHz) δ 12.20 (s, 1H), 7.95 (d, 1H, J = 2.6 Hz), 3.81 (s, 2H), 2.45 (s, 3H),
1.91 (s, 3H), 1.64-1.51 (m, 12H). 13C NMR (DMSO, 75 MHz) δ 156.6 (C), 150.5 (C), 149.2
(C), 144.8 (CH), 122.8 (C), 54.3 (CH2), 40.7 (3 CH2), 36.6 (3 CH2), 36.0 (C), 28.0 (3 CH),
14.8 (CH3). LC-MS (ESI) m/z 299.2 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C17H24N4O 299.1866 ; found 299.1871.
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8-Butyl-9-(prop-2-yn-1-yl)-6,9-dihydro-1H-purin-6-one (14). Compound 14 (Y = 37%, 129
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mg from 300 mg (1.9 mmol) of 8) was isolated as a beige solid ; mp > 250 °C. H NMR
(DMSO, 300 MHz) δ 12.29 (s, 1H), 8.01 (s, 1H), 4.98 (d, 2H, J = 2.5 Hz), 3.45 (t, 1H, J = 2.5
Hz), 2.50 (s, 3H). 13C NMR (DMSO, 75 MHz) δ 156.5 (C), 149.0 (C), 148.1 (C), 145.7 (CH),
123.0 (C), 78.2 (C), 76.1 (CH), 31.9 (CH2), 13.9 (CH3). LC-MS (ESI) m/z 189.1 [M+H]+.
HRMS (ESI-TOF) m/z [M+H]+ calcd for C9H9N4O 189.0771 ; found 189.0776.
General Procedure for the Synthesis of 6-amino-8,9-disubstituted-3,9-dihydro-2H-
purin-2-ones (15-20). 5-Amino-1,2-disubstituted-1H-imidazole-4-carbonitrile (1-4 or 6-7) (3.8
mmol) and urea (7.6 mmol) were heated at 135-180 °C according to the starting imidazole
melting point and the mixture was stirred 24 h. The temperature was lowered to 100-110 °C
and water (10 mL) was added. The resulting mixture was stirred for 1 h. The resulting
precipitate was filtered and washed with water and with dichloromethane.
6-Amino-9-benzyl-8-methyl-3,9-dihydro-2H-purin-2-one (15). The precipitate was purified
on silica gel chromatography eluting with 15% methanol in dichloromethane. Compound 15
(Y = 37%, 360 mg from 800 mg (3.8 mmol) of 1) was isolated as a beige solid ; mp > 250 °C.
1H NMR (DMSO, 300 MHz) δ 10.27 (s, 1H), 7.39-7.27 (m, 4H), 7.24-7.16 (m, 2H), 5.75 (s,
1H), 5.11 (s, 2H), 2.24 (s, 3H). 13C NMR (DMSO, 75 MHz) δ 155.9 (C), 150.6 (C), 150.5 (C),
146.8 (C), 137.0 (C), 128.7 (2CH), 127.4 (CH), 126.8 (2CH), 107.4 (C), 44.2 (CH2), 13.7
(CH3). LC-MS (APCI+) m/z 256.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H14N5O
256.1193 ; found 256.1197.
6-Amino-9-benzyl-8-butyl-3,9-dihydro-2H-purin-2-one (16). The precipitate was washed in
hot ethanol. Compound 16 (Y = 38%, 220 mg from 500 mg (2.0 mmol) of 2) was isolated as
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a beige solid ; mp > 250 °C. H NMR (DMSO, 300 MHz) δ 10.80 (s, 1H), 7.57 (s, 2H), 7.32-
7.26 (m, 3H), 7.16-7.14 (m, 2H), 5.13 (s, 1H), 2.55 (t, 2H, J = 7.3 Hz), 1.50 (quint, 2H, J = 7.3
Hz), 1.25 (sex, 2H, J = 7.2 Hz), 0.78 (t, 3H, J = 7.0 Hz). 13C NMR (DMSO, 125 MHz) δ 158.1
(C), 156.3 (C), 153.0 (C), 150.2 (C), 137.3 (C), 128.7 (2CH), 127.4 (CH), 126.7 (2CH), 126.2
(C), 44.0 (CH2), 28.7 (CH2), 26.5 (CH2), 21.7 (CH2), 13.6 (CH3). LC-MS (APCI+) m/z 298.1
[M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C16H18N5O 298.1662 ; found 296.1666.
6-Amino-8-methyl-9-phenylethyl-3,9-dihydro-2H-purin-2-one (17). The precipitate was
washed in hot ethanol. Compound 17 (Y = 47%, 235 mg from 420 mg (1.9 mmol) of 3) was
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isolated as a beige solid ; mp > 250 °C. H NMR (DMSO, 300 MHz) δ 10.49 (s, 1H), 7.36-
7.22 (m, 5H), 7.20-7.11 (m, 2H), 4.06 (t, 2H, J = 7.0 Hz), 2.95 (t, 2H, J = 7.0 Hz), 1.98 (s,
3H). 13C NMR (DMSO, 125 MHz) δ 156.8 (C), 156.0 (C), 150.0 (C), 146.8 (C), 138.3 (C),
128.9 (2CH), 128.5 (2CH), 126.6 (CH), 107.3 (C), 43.2 (CH2), 34.6 (CH2), 13.12 (CH3). LC-
MS (ESI) m/z 270.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C14H16N5O 270.1349 ;
found 270.1335.
6-Amino-8-butyl-9-phenylethyl-3,9-dihydro-2H-purin-2-one (18). The precipitate was
washed in hot acetonitrile. Compound 18 (Y = 40%, 185 mg from 400 mg (1.5 mmol) of 4)
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was isolated as a beige solid ; mp > 250 °C. H NMR (DMSO, 300 MHz) δ 10.59 (s, 1H),
7.41 (s, 2H), 7.30-7.19 (m, 3H), 7.12-7.10 (m, 2H), 4.06 (t, 2H, J = 7.0 Hz), 2.96 (t, 2H, J =
7.0 Hz), 2.27 (t, 2H, J = 7.5 Hz), 1.53-1.43 (quint, 2H, J = 7.6 Hz), 1.30-1.18 (sex, 2H, J = 7.4
Hz), 0.83 (t, 3H, J = 7.3 Hz). 13C NMR (DMSO, 75 MHz) δ 156.1 (C), 156.0 (C), 150.8 (C),
150.1 (C), 138.3 (C), 128.9 (2CH), 128.4 (2CH), 126.5 (CH), 107.7 (C), 43.1 (CH2), 34.7
(CH2), 28.6 (CH2), 25.9 (CH2), 21.8 (CH2), 13.7 (CH3). LC-MS (ESI) m/z 312.2 [M+H]+. HRMS
(ESI-TOF) m/z [M-H]+ calcd for C17H20N5O 312.1819 ; found 312.1823.
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6-Amino-9-(adamantan-1-ylmethyl)-8-methyl-3,9-dihydro-2H-purin-2-one (19). The crude
residue was isolated and purified on preparative HPLC. Compound 19 (Y = 21%, 96 mg from
400 mg (1.5 mmol) of 6) was isolated as a beige solid ; mp > 250 °C. H NMR (DMSO, 300
MHz) δ 10.53 (s, 1H), 7.41 (s, 2H), 3.58 (s, 2H), 2.36 (s, 3H), 1.92 (s, 3H), 1.65-1.52 (m,
12H). 13C NMR (DMSO, 75 MHz) δ 156.4 (C), 151.4 (C), 151.0 (C), 148.0 (C), 108.2 (C),
53.4 (CH2), 40.8 (3 CH2), 36.7 (3 CH2), 36.1 (C), 28.1 (3 CH), 14.9 (CH3). LC-MS (ESI) m/z
314.2 [M+H]+. HRMS (ESI-TOF) m/z [M-H]- calcd for C17H22N5O 312.1819 ; found 312.1823.
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6-Amino-8-butyl-9-propyl-3,9-dihydro-2H-purin-2-one (20). The crude residue was
purified on silica gel chromatography eluting with 5% ammonia saturated methanol in
dichloromethane and washed with ethanol. Compound 20 (Y = 33%, 80 mg from 200 mg
(0.97 mmol) of 7) was isolated as a beige solid ; mp > 250 °C. 1H NMR (DMSO, 300 MHz) δ
10.41 (s, 1H), 7.35 (s, 2H), 3.81 (m, 2H), 2.67 (t, 2H, J = 7.6 Hz), 1.68-1.63 (m, 4H), 1.42-
1.34 (m, 2H), 0.93-0.85 (m, 6H). 13C NMR (DMSO, 75 MHz) δ 155.9 (C), 155.3 (C), 151.3
(C), 150.6 (C), 108.0 (C), 43.3 (CH2), 29.4 (CH2), 26.7 (CH2), 22.8 (CH2), 22.3 (CH2), 14.2
(CH3), 11.4 (CH3). LC-MS (ESI) m/z 250.2 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C12H20N5O 250.1662 ; found 250.1672.
General Procedure for the Synthesis of 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-
diamines (21-24). Imidazole (1-2, 6-7) (1.4 mmol) and guanidine carbonate (2.8 mmol) were
heated at 175 °C for 20 min. The temperature was raised to 200 °C and the mixture was
stirred for 2 h. The reaction mixture was poured in hot water (20 mL) and the mixture was
stirred for 10 min.
9-Benzyl-8-methyl-3,9-dihydro-2H-purin-2,6-diamine (21). After return to room
temperature, the residue was extracted with ethyl acetate (3 x 15 mL). The organic layer was
washed with saturated aqueous NaCl (3 x 15 mL), dried over MgSO4 and the solvent was
evaporated under reduced pressure. The crude residue was purified on silica gel
chromatography eluting with 10% ethanol in ethyl acetate and washed with diethyl ether.
Compound 21 (Y = 56%, 200 mg from 300 mg (1.4 mmol) of 1) was isolated as a beige solid
; mp = 247-249 °C. 1H NMR (DMSO, 300 MHz) δ 7.32-7.25 (m, 3H), 7.14-7.12 (m, 2H), 6.60
(s, 2H), 5.73 (s, 2H), 5.17 (s, 2H), 2.27 (s, 3H). 13C NMR (DMSO, 75 MHz) δ 160.4 (C), 155.7
(C), 153.5 (C), 145.2 (C), 137.8 (C), 129.1 (2CH), 127.8 (CH), 127.1 (2CH), 112.2 (C), 44.7
(CH2), 14.0 (CH3). LC-MS (ESI) m/z 255.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C13H15N6 255.1353 ; found 255.1346.
9-Benzyl-8-butyl-3,9-dihydro-2H-purin-2,6-diamine (22). After return to room temperature,
the residue was extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with
saturated aqueous NaCl (3 x 15 mL), dried over MgSO4 and the solvent was evaporated
under reduced pressure. The crude residue was purified on silica gel chromatography eluting
with 20% ethanol in ethyl acetate and washed with diethyl ether. Compound 22 (Y = 23%, 80
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mg from 300 mg (1.2 mmol) of 2) was isolated as a beige solid ; mp = 196-198 °C. H NMR
(DMSO, 300 MHz) δ 7.34-7.22 (m, 3H), 7.12-7.09 (m, 2H), 6.58 (s, 2H), 5.72 (s, 2H), 5.19 (s,
2H), 2.28 (t, 2H, J = 7.7 Hz), 1.56-1. 46 (quint, 2H, J = 7.5 Hz), 1.31-1.19 (sex, 2H, J = 7.4
Hz), 0.78 (t, 3H, J = 7.3 Hz). 13C NMR (DMSO, 75 MHz) δ 160.4 (C), 155.8 (C), 153.5 (C),
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148.7 (C), 138.0 (C), 129.1 (2CH), 127.8 (CH), 126.9 (2CH), 112.3 (C), 44.6 (CH2), 29.46
(CH2), 26.9 (CH2), 22.2 (CH2), 14.1 (CH3). LC-MS (ESI) m/z 297.2 [M+H]+. HRMS (ESI-TOF)
m/z [M+H]+ calcd for C16H21N6 297.1822 ; found 297.1826.
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9-(Adamantan-1-ylmethyl)-8-methyl-3,9-dihydro-2H-purin-2,6-diamine (23). After return
to room temperature, the precipitate was filtered, washed with water and with
dichloromethane. Then, the precipitate was purified on thick-layer chromatography eluting
with 15% ethanol in ethyl acetate. Compound 23 (Y = 62%, 215 mg from 300 mg (1.1 mmol)
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of 6) was isolated as a beige solid ; mp > 250 °C. H NMR (DMSO, 300 MHz) δ 12.20 (s,
1H), 7.95 (d, 1H, J = 2.6 Hz), 3.81 (s, 2H), 2.45 (s, 3H), 1.91 (s, 3H), 1.64-1.51 (m, 12H). 13C
NMR (DMSO, 75 MHz) δ 160.0 (C), 155.5 (C), 154.4 (C), 146.0 (C), 122.3 (C), 53.5 (CH2),
40.9 (3 CH2), 36.7 (3 CH2), 36.1 (C), 28.1 (3 CH), 14.8 (CH3). LC-MS (ESI) m/z 313.3
[M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C17H25N6 313.2135 ; found 313.2143.
8-Butyl-9-propyl-3,9-dihydro-2H-purin-2,6-diamine (24). After return to room temperature,
the precipitate was filtered, washed with water and the crude residue was purified on thick-
layer chromatography eluting with 10% ethanol in ethyl acetate. Compound 24 (Y = 44%,
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106 mg from 200 mg (0.97 mmol) of 7) was isolated as a beige solid ; mp = 171-173 °C. H
NMR (DMSO, 300 MHz) δ 6.45 (s, 2H), 5.64 (s, 2H), 3.85 (t, 2H, J = 7.4 Hz), 2,69 (t, 2H J =
7.6 Hz), 1.74-1.61 (m, 4H), 1.44-1.32 (sex, 2H, J = 7.4 Hz), 0.93-0.82 (m, 6H). 13C NMR
(DMSO, 75 MHz) δ 160.1 (C), 155.6 (C), 153.2 (C), 148.6 (C), 112.4 (C), 43.3 (CH2), 29.8
(CH2), 26.7 (CH2), 23.1 (CH2), 22.3 (CH2), 14.3 (CH3), 11.5 (CH3). LC-MS (ESI) m/z 249.2
[M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C12H21N6 249.1822 ; found 249.1831.
Synthesis of 9-benzyl-6-imino-8-methyl-1-phenyl-6,9-dihydro-1H-purin-2-(3H)-one (25).
5-Amino-1-benzyl-2-methyl-1H-imidazole-4-carbonitrile 1 (0.9 mmol) was dissolved in THF
(10 mL) containing triethylamine (0.45 mmol). This solution was slowly added dropwise in a
solution of phenylisocyanate (9.4 mmol) in THF (5 mL). Then, the mixture was stirred at room
temperature during 7 days. The solvent was evaporated and the residue was dissolved in
DCM (10 mL). The organic layer was washed with saturated aqueous NaCl (3 x 10 mL),
dried over CaCl2 and was evaporated under reduced pressure. The crude residue was
purified on silica gel chromatography eluting with 10% ethanol in ethyl acetate. Compound
25 (Y = 13%, 40 mg from 200 mg (0.9 mmol) of 1) was isolated as a beige solid ; mp > 250
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°C. H NMR (DMSO, 300 MHz) δ 7.55-7.23 (m, 12H), 5.13 (s, 2H), 2.29 (s, 3H). 13C NMR
(DMSO, 125 MHz) δ 155.7 (C), 154.7 (C), 150.8 (C), 147.1 (C), 137.5 (C), 136.9 (C), 130.3
(2CH), 129.3 (2CH), 129.2 (2CH), 129.1 (CH), 128.0 (CH), 127.5 (2CH), 107.0 (C), 44.5
(CH2), 14.2 (CH3). LC-MS (ESI) m/z 332.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C19H18N5O 332.1506 ; found 332.1509.
Synthesis of 9-benzyl-8-butyl-6-imino-1-phenyl-6,9-dihydro-1H-purin-2-(3H)-one (26). 5-
Amino-1-benzyl-2-butyl-1H-imidazole-4-carbonitrile 2 (0.4 mmol) was dissolved in DCM (5
mL) containing few drops of triethylamine. To this solution was added phenylisocyanate (0.5
mmol) and the mixture was stirred at room temperature during 12 days. The organic layer
was washed with saturated aqueous NaCl (3 x 5 mL), dried over CaCl2 and was evaporated
under reduced pressure. The crude residue was purified on silica gel chromatography eluting
with 10% ethanol in ethyl acetate. Compound 26 (Y = 7%,11 mg from 100 mg (0.4 mmol) of
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2) was isolated as a beige solid ; mp > 250 °C. H NMR (DMSO, 500 MHz) δ 7.54-7.24 (m,
12H), 5.17 (s, 2H), 2.61 (t, 2H, J = 7.5 Hz), 1.55-1.49 (quint, 2H, J = 7.5 Hz), 1.31-1.27 (m,
2H), 0.81 (t, 3H, J = 7.3 Hz). 13C NMR (DMSO, 125 MHz) δ 155.3 (C), 154.8 (C), 150.9 (C),
150.6 (C), 137.7 (C), 136.9 (C), 130.3 (2CH), 129.3 (2CH), 129.1 (3CH), 127.9 (CH), 127.3
(2CH), 106.7 (C), 44.4 (CH2), 29.3 (CH2), 27.0 (CH2), 22.2 (CH2), 14.1 (CH3). LC-MS (ESI)
m/z 374.2 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C22H24N5O 374.1934 ; found
374.1939.
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General Procedure for the Synthesis of N'-(4-cyano-1,2-disubstituted-1H-imidazol-5-
yl)-N,N-dimethylmethanimidamides (34-38). 5-Amino-1,2-disubstituted-1H-imidazole-4-
carbonitrile (1-3 or 5-6) (1.7 mmol) was dissolved in N,N-dimethylformamide dimethylacetal
(DMF-DMA, 3 mL) and the solution was irradiated at 70 °C (200 W) for 15 min in a sealed
vessel. After return to room temperature, the mixture was poured into water (30 mL) and the
residue was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with
water (2 x 20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4 and the solvent
evaporated under reduced pressure.
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N'-(1-Benzyl-4-cyano-2-methyl-1H-imidazol-5-yl)-N,N-dimethylmethanimidamide
(34).
The crude residue was purified on silica gel chromatography eluting with 30% cyclohexane in
ethyl acetate. Compound 34 (Y = 97%, 450 mg from 370 mg (1.7 mmol) of 1) was isolated as
a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.21 (s, 1H), 7.34-7.29 (m, 3H), 7.11-7.08 (m, 2H),
5.03 (s, 2H), 3.08 (s, 3H), 3.00 (s, 3H), 2.19 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 155.0 (CH),
150.1 (C), 142.1 (C), 136.3 (C), 128.8 (2CH), 127.7 (CH), 126.8 (2CH), 118.3 (C), 93.1 (C),
45.7 (CH2), 40.6 (CH3), 34.3 (CH3), 14.0 (CH3). LC-MS (APCI+) m/z 268.2 [M+H]+. HRMS
(ESI-TOF) m/z [M+H]+ calcd for C15H18N5 268.1557 ; found 268.1561.
N'-(1-Benzyl-2-butyl-4-cyano-1H-imidazol-5-yl)-N,N-dimethylmethanimidamide (35). The
crude residue was purified on silica gel chromatography eluting with 30% cyclohexane in
ethyl acetate. Compound 35 (Y = 97%, 590 mg from 500 mg (2.0 mmol) of 2) was isolated as
a purple solid ; mp = 83-85 °C. 1H NMR (CDCl3, 300 MHz) δ 8.22 (s, 1H), 7.32-7.29 (m, 3H),
7.10-7.07 (m, 2H), 5.06 (s, 2H), 3.09 (s, 3H), 2.99 (s, 3H), 2.46 (t, 2H, J = 7.8 Hz), 1.63-1.53
(m, 2H), 1.30 (sex, 2H, J = 7.5 Hz), 0.85 (t, 3H, J = 7.3 Hz). 13C NMR (CDCl3, 75 MHz) δ
155.0 (CH), 149.9 (C), 145.9 (C), 136.6 (C), 128.8 (2CH), 127.7 (CH), 126.6 (2CH), 118.2
(C), 93.2 (C), 45.5 (CH2), 40.6 (CH3), 34.3 (CH3), 29.2 (CH2), 27.3 (CH2), 22.3 (CH2), 13.7
(CH3). LC-MS (APCI+) m/z 310.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C18H24N5 310.2026 ; found 310.2027.
N'-(4-Cyano-2-methyl-1-phenylethyl-1H-imidazol-5-yl)-N,N-dimethylmethanimidamide
(36). The crude residue was purified on silica gel chromatography eluting with 30%
cyclohexane in ethyl acetate. Compound 36 (Y = 84%, 420 mg from 400 mg (1.8 mmol) of 3)
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was isolated as a beige solid ; mp = 98-100 °C. H NMR (CDCl3, 300 MHz) δ 7.91 (s, 1H),
7.29-7.22 (m, 3H), 7.03-6.98 (m, 2H), 4.01 (t, 2H, J = 6.9 Hz), 3.04 (s, 3H), 3.01 (s, 3H), 2.92
(t, 2H, J = 6.9 Hz), 2.06 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 154.6 (CH), 150.0 (C), 141.7
(C), 137.8 (C), 128.9 (2CH), 128.6 (2CH), 126.7 (CH), 118.2 (C), 93.2 (C), 44.4 (CH2), 40.5
(CH3), 35.9 (CH2), 34.2 (CH3), 13.4 (CH3). LC-MS (APCI+) m/z 282.2 [M+H]+. HRMS (ESI-
TOF) m/z [M+H]+ calcd for C16H20N5 282.1713 ; found 282.1715.
N'-(4-Cyano-1-phenylethyl-2-propyl-1H-imidazol-5-yl)-N,N-dimethylmethanimidamide
(37). The crude residue was purified on silica gel chromatography eluting with 30%
cyclohexane in ethyl acetate. Compound 37 (Y = 97%, 470 mg from 400 mg (1.6 mmol) of 5)
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was isolated as an orange oil. H NMR (CDCl3, 300 MHz) δ 7.89 (s, 1H), 7.28-7.22 (m, 3H),
7.03-7.00 (m, 2H), 4.02 (t, 2H, J = 7.1 Hz), 3.04 (s, 3H), 3.01 (s, 3H), 2.92 (t, 2H, J = 7.1 Hz),
2.34 (t, 2H, J = 7.7 Hz), 1.67 (sex, 2H, J = 7.4 Hz), 0.94 (t, 3H, J = 7.4 Hz). 1H NMR (CDCl3,
300 MHz) δ 7.91 (s, 1H), 7.29-7.22 (m, 3H), 7.03-6.98 (m, 2H), 4.01 (t, 2H, J = 6.9 Hz), 3.04
(s, 3H), 3.01 (s, 3H), 2.92 (t, 2H, J = 6.9 Hz), 2.06 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 154.6
(CH), 150.0 (C), 145.2 (C), 137.9 (C), 128.9 (2CH), 128.6 (2CH), 126.6 (CH), 118.4 (C), 93.5
(C), 44.1 (CH2), 40.5 (CH3), 36.2 (CH2), 34.2 (CH3), 29.1 (CH2), 20.7 (CH2), 13.4 (CH3). LC-
MS (APCI+) m/z 310.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C18H24N5 310.2026 ;
found 310.2028.
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N'-(1-Adamantan-1-ylmethyl)-4-cyano-2-methyl-1H-imidazol-5-yl)-N,N-
dimethylmethanimidamide (38). For this compound, the mixture was poured into water (30
mL). The resulting precipitate was filtered and washed with water. Compound 38 (Y = 83%,
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400 mg from 400 mg (1.5 mmol) of 6) was isolated as a beige solid; mp = 198-200 °C. H
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NMR (DMSO, 300 MHz) ) δ 8.02 (s, 1H), 3.52 (s, 2H), 3.06 (s, 3H), 2.97 (s, 3H), 2.23 (s, 3H),
1.91 (s, 3H), 1.64-1.47 (m, 12H). 13C NMR (DMSO, 75 MHz) δ 155.5 (CH), 151.9 (C), 143.1
(C), 1118.9 (C), 93.2 (C), 53.9 (CH2), 40.2 (3CH2), 36.6 (3CH2), 36.0 (C), 34.5 (2CH3), 28.1
(3CH), 14.9 (CH3). LC-MS (ESI) m/z 326,2 (MH+). HRMS (ESI-TOF) m/z [M+H]+ calcd for
C19H28N5 326.2339 ; found 326.2347.
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General Procedure for the Synthesis of 8,9-disubstituted-9H-purin-6-amines (27-31):
N'-(4-Cyano-1,2-disubstituted-1H-imidazol-5-yl)-N,N-dimethylmethanimidamide (34-38) (1.5
mmol) was dissolved in formamide (3 mL). The solution was irradiated at 170 °C (200 W) for
30 min in a sealed vessel. After return to room temperature, the mixture was poured into
water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was extracted
with 1N aqueous HCl (3 x 20 mL). Then, the aqueous layer was neutralized with 1N aqueous
NaOH (20 mL) and was extracted with ethyl acetate (3 x 20 mL). The organic layer was
washed with water (2 x 20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4 and
the solvent was evaporated under reduced pressure.
9-Benzyl-8-methyl-9H-purin-6-amine (27). The precipitate was purified on silica gel
chromatography eluting with 10% ethanol in ethyl acetate and then, on thick-layer
chromatography eluting with 10% ethanol in ethyl acetate. Compound 27 (Y = 74%, 270 mg
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from 410 mg (1.5 mmol) of 34) was isolated as a beige solid ; mp = 238-240 °C. H NMR
(DMSO, 300 MHz) δ 8.12 (s, 1H), 7.35-7.24 (m, 3H), 7.19-7.14 (m, 4H), 5.35 (s, 2H), 2.41 (s,
3H). 13C NMR (DMSO, 75 MHz) δ 155.5 (C), 152.4 (C), 151.2 (CH), 149.0 (C), 137.3 (C),
129.2 (2CH), 128.0 (CH), 127.4 (2CH), 118.0 (C), 45.3 (CH2), 14.2 (CH3). LC-MS (APCI+)
m/z 240.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H14N5 240.1244 ; found
240.1249.
9-Benzyl-8-butyl-9H-purin-6-amine (28). The precipitate was recrystallized from
acetonitrile. Compound 28 (Y = 68%, 309 mg from 500 mg (1.6 mmol) of 35) was isolated as
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a beige solid ; mp = 134-136 °C. H NMR (DMSO, 300 MHz) δ 8.10 (s, 1H), 7.34-7.22 (m,
3H), 7.16-7.09 (m, 2H), 7.09 (s, 2H), 5.36 (s, 2H), 2.72 (t, 3H, J = 7.6 Hz), 1.57 (quint, 2H, J
= 7.6 Hz), 1.27 (sex, 2H, J = 7.4 Hz), 0.80 (t, 3H, J = 7.3 Hz). 13C NMR (DMSO, 75 MHz) δ
155.5 (C), 152.4 (1C and 1CH), 151.2 (C), 137.5 (C), 129.2 (2CH), 128.0 (CH), 127.2 (2CH),
118.1 (C), 45.1 (CH2), 29.3 (CH2), 27.0 (CH2), 22.2 (CH2), 14.1 (CH3). LC-MS (APCI+) m/z
282.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C16H20N5 282.1713 ; found 282.1711.
8-Methyl-9-phenylethyl-9H-purin-6-amine (29). The precipitate was purified on thick-layer
chromatography eluting with 8% methanol in dichloromethane. Compound 29 (Y = 70%, 189
mg from 300 mg (1.1 mmol) of 36) was isolated as a beige solid ; mp = 197-199 °C. 1H NMR
(DMSO, 300 MHz) δ 8.10 (s, 1H), 7.25-7.29 (m, 3H), 7.07-7.05 (m, 2H), 7.00 (s, 2H), 4.28 (t,
2H, J = 7.0 Hz), 3.02 (t, 2H, J = 7.0 Hz), 2.13 (s, 3H). 13C NMR (DMSO, 75 MHz) δ 155.3 (C),
152.1 (C), 150.9 (CH), 148.9 (C), 138.6 (C), 129.3 (2CH), 128.9 (2CH), 127.0 (CH), 118.1
(C), 44.1 (CH2), 35.4 (CH2), 13.6 (CH3). LC-MS (APCI+) m/z 254.0 [M+H]+. HRMS (ESI-TOF)
m/z [M+H]+ calcd for C14H16N5 254.1400 ; found 254.1406.
9-Phenylethyl-8-propyl-9H-purin-6-amine (30). The precipitate was purified on thick-layer
chromatography eluting with 10% ethanol in ethyl acetate. Compound 30 (Y = 72%, 295 mg
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from 450 mg (1.45 mmol) of 37) was isolated as a beige solid ; mp > 250 °C. H NMR
(DMSO, 300 MHz) δ 8.11 (s, 1H), 7.28-7.19 (m, 3H), 7.08-7.02 (m, 4H), 4.30 (t, 2H, J = 7.0
Hz), 3.04 (t, 2H, J = 7.0 Hz), 2.43 (t, 2H, J = 7.5 Hz), 1.59 (sex, 2H, J = 7.4 Hz), 0.85 (t, 3H, J
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= 7.4 Hz). 13C NMR (DMSO, 75 MHz) δ 155.4 (C), 152.1 (1C et 1CH), 150.9 (C), 138.6 (C),
129.3 (2CH), 128.9 (2CH), 127.0 (CH), 118.2 (C), 43.9 (CH2), 35.5 (CH2), 28.7 (CH2), 20.5
(CH2), 14.2 (CH3). LC-MS (APCI+) m/z 282.1 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C16H20N5 282.1713 ; found 282.1720.
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9-(Adamantan-1-ylmethyl)-8-methyl-9H-purin-6-amine (31). The precipitate was purified
on silica gel chromatography eluting with 10% ethanol in ethyl acetate. Compound 31 (Y =
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72%, 100 mg from 150 mg (0.46 mmol) of 38) was isolated as white solid ; mp > 250 °C. H
NMR (DMSO, 300 MHz) 8.05 (s, 1H), 7.00 (s, 2H), 3.80 (s, 2H), 2.49 (s, 3H), 1.91 (s, 3H),
1.64-1.53 (m, 12H). 13C NMR (DMSO, 75 MHz) δ 155.4 (C), 152.2 (C), 151.1 (CH), 149.8
(C), 118.0 (C), 54.0 (CH2), 40.8 (3CH2), 36.6 (3CH2), 36.1 (C), 28.1 (3CH), 14.9 (CH3). LC-
MS (ESI) m/z 298.2 (MH+). HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H24N5 298.2026 ;
found 298.2034.
General Procedure for the Synthesis of N-(6-imino-8,9-disubstituted-6,9-dihydro-1H-
purin-1-yl)(tert-butoxy)formamides (39-40). 5-Amino-1,2-disubstituted-1H-imidazole-4-
carbonitrile (1-2) (3.3 mmol) was dissolved in triethyl orthoformate (8 mL). The mixture was
refluxed for 6 h. After return to room temperature, the mixture was evaporated under reduced
pressure and dissolved in cold ethanol (5 mL). The tert-butyl carbazate (9.9 mmol) was
added at 0-5 °C. The mixture was stirred at room temperature for 7 days. Then, the reaction
mixture was poured in water (50 mL). The resulting precipitate was filtered, washed with
water and purified on silica gel chromatography eluting with 10% ethanol in ethyl acetate.
N-(9-Benzyl-6-imino-8-methyl-6,9-dihydro-1H-purin-1-yl)(tert-butoxy)formamide
(39).
Compound 39 (Y = 64%, 750 mg from 700 mg (3.3 mmol) of 1) was isolated as a beige solid
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; mp = 229-231 °C. H NMR (DMSO, 300 MHz) δ 8.58 (m, 1H), 7.38-7.19 (m, 6H), 5.37 (s,
2H), 2.42 (s, 3H), 1.40 (s, 9H). LC-MS (ESI) m/z 299.1 [M-tBu+2H]+ and 355.2 [M+H]+.
N-(9-Benzyl-8-butyl-6-imino-6,9-dihydro-1H-purin-1-yl)(tert-butoxy)formamide
(40).
Compound 40 (Y = 60%, 285 mg from 300 mg (1.2 mmol) of 2) was isolated as a light
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orange solid ; mp = 199-201 °C. H NMR (CDCl3, 300 MHz) δ 8.59 (s, 1H), 8.14 (s, 1H),
7.37-7.28 (m, 3H), 7.18-7.15 (m, 2H), 5.38 (s, 2H), 2.72 (t, 2H, J = 7.5 Hz), 1.60-1.50 (quint,
2H, J = 7,5 Hz), 1.40 (s, 9H), 1.34-1.24 (sex, 2H, J = 7,4 Hz), 0.79 (t, 3H, J =7.4 Hz). LC-MS
(ESI) m/z 341.2 [M-tBu+2H]+ and 397.2 [M+H]+.
General Procedure for the Synthesis of N-(6-imino-8,9-disubstituted-6,9-dihydro-1H-
purin-1-aminium-2,2,2-trifluoroacetates (32-33). N-(6-Imino-8,9-disubstituted-6,9-dihydro-
1H-purin-1-yl)(tert-butoxy)formamide (39-40) (2.1 mmol) was dissolved in dichloromethane
(15 mL) and trifluoroacetic acid (2.5 mL) was added. The mixture was stirred at room
temperature for 24 h. The solvent was removed under reduced pressure and the residue was
dissolved in diethyl ether (3 mL). The resulting precipitate was filtered, washed with diethyl
ether.
9-Benzyl-6-imino-8-methyl-6,9-dihydro-1H-purin-1-aminium-2,2,2-trifluoroacetate (32).
Compound 32 (Y = 86%, 650 mg from 730 mg (2.1 mmol) of 39) was isolated as a beige
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solid ; mp 195-197 °C. H NMR (DMSO, 300 MHz) δ 9.93 (s, 1H, OH, TFA), 9.05 (s, 1H),
8.61 (s, 1H), 7.39-7.31 (m, 3H), 7.23-7.21 (m, 2H), 6.56 (s, 2H), 5.47 (s, 2H), 2.52 (s, 3H).
13C NMR (DMSO, 75 MHz) δ 153.0 (C), 150.7 (C), 148.4 (CH), 147.1 (C), 135.5 (C), 128.9
(2CH), 128.0 (CH), 127.1 (2CH), 117.1 (C), 45.6 (CH2), 14.0 (CH3). LC-MS (ESI) m/z 255.1
[M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H15N6+ 255.1353 ; found 255.1346.
9-Benzyl-8-butyl-6-imino-6,9-dihydro-1H-purin-1-aminium-2,2,2-trifluoroacetate
(33).
Compound 33 (Y = 68%, 105 mg from 150 mg (0.4 mmol) of 40) was isolated as a beige
solid ; mp 213-215 °C. 1H NMR (DMSO, 300 MHz) δ 9.89 (s, 1H, OH,TFA), 9.04 (s, 1H), 8.61
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(s, 1H), 7.35-7.32 (m, 3H), 7.20-7.17 (m, 2H), 6.55 (s, 2H), 5.49 (s, 2H), 2.83 (t, 2H, J = 7.6
Hz), 1.63-1.53 (quint, 2H, J = 7.6 Hz), 1.35-1.23 (sex, 2H, J = 7.4 Hz), 0.80 (t, 3H, J = 7.4
Hz). 13C NMR (DMSO, 75 MHz) δ 155.4 (C), 151.3 (C), 148.3 (CH), 146.4 (C), 136.0 (C),
128.9 (2CH), 128.0 (CH), 126.9 (2CH), 117.8 (C), 45.5 (CH2), 28.7 (CH2), 26.7 (CH2), 21.7
(CH2), 13.6 (CH3). LC-MS (ESI) m/z 297.2 [M+H]+. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C16H21N6+ 297.1743 ; found 297.1750.
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3-Benzyl-2-methyl-3H-[1,2,4]triazolo[5,1-i]purine
(48).
Compound 48 (Y = 5%, 11 mg from 180 mg (0.8 mmol) of 1) was isolated as a beige solid ;
1H NMR (DMSO, 300 MHz) δ 9.64 (s, 1H), 9.04 (s, 1H), 8.60 (s, 1H), 7.33-7.31 (m, 3H),
7.23-7.21 (m, 2H), 5.58 (s, 2H), 2.55 (s, 3H). LC-MS (ESI) m/z 265.1 [M+H]+.
3-Benzyl-2-butyl-3H-[1,2,4]triazolo[5,1-i]purine
(49).
Compound 49 (Y = 3%, 10 mg from 300 mg (1.2 mmol) of 2) was isolated as a beige solid
1H NMR (DMSO, 300 MHz) δ 9.63 (s, 1H), 8.61 (s, 1H), 7.35-7.24 (m, 3H), 7.20-7.17 (m,
2H), 5.60 (s, 2H), 2.85 (t, 2H, J = 7.6 Hz), 1.65 (quint, 2H, J = 7.5 Hz), 1.31 (sex, 2H, J = 7.4
Hz), 0.82 (t, 3H, J = 7.3 Hz). LC-MS (ESI) m/z 307.2 [M+H]+.
ASSOCIATED CONTENT
Supporting information
Copies of 1H and 13C NMR spectra for all new compounds (PDF).
AUTHOR INFORMATION
Corresponding Authors
* E-mail: natascha.leleu-2@univ-lille2.fr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We gratefully acknowledge the “Ecole Doctorale Biologie-Santé de Lille” for doctoral
research allowance to Mélanie Bollier and the financial support of StartAIRR. The authors
thank Dr. Audrey Hottin for assistance during the preparation of the manuscript.
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